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New research suggests cutaneous T-cell lymphoma (CTCL) is driven by a plethora of genetic mutations.
Investigators conducted a genomic analysis of normal and cancer cells from patients with CTCL and identified mutations in 17 genes that are implicated in CTCL pathogenesis.
They also found that somatic copy number variants (SCNVs) driving CTCL outnumbered somatic single-nucleotide variants (SSNVs) by more than 10 to 1.
The team reported these findings in Nature Genetics.
They performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL cells and matched normal cells. And they identified genes implicated in CTCL pathogenesis by looking for:
- Genes with recurrent SSNVs altering the same amino acid more often than expected by chance
- Genes with SSNVs previously identified as recurrent mutations in other cancers
- Genes having a significantly increased burden of protein-altering SSNVs
- SCNVs that occurred more often than expected by chance.
This revealed mutations in 17 genes that are implicated in CTCL pathogenesis—TP53, ZEB1, ARID1A, DNMT3A, CDKN2A, FAS, NFKB2, CD28, RHOA, PLCG1, STAT5B, BRAF, ATM, CTCF, TNFAIP3, PRKCQ, and IRF4.
The investigators noted that these are genes involved in T-cell activation, apoptosis, NF-κB signaling, chromatin remodeling, and DNA damage response.
The team also discovered “a striking bias” for SCNVs as drivers of CTCL. They identified 12 statistically significant chromosome-arm SCNVs and 36 significant focal SCNVs.
Collectively, these SCNVs occurred 473 times in the CTCL samples analyzed—a mean of 7.5 focal deletions, 1.6 broad deletions, 1.0 focal amplification, and 1.8 broad amplifications per CTCL.
On the other hand, there were 38 SSNVs in CTCL driver genes—1.0 per tumor.
So, according to these data, SCNVs comprise 92% of all driver mutations in CTCL—a mean of 11.8 pathogenic SCNVs vs 1.0 SSNV per CTCL.
“This cancer has a very distinctive biology,” said Jaehyuk Choi, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut.
And decoding this biology has revealed potential treatment approaches, according to Dr Choi and his colleagues.
For example, the presence of mutations activating the NF-κB pathway suggests NF-κB inhibitors such as bortezomib may have therapeutic potential in CTCL, and the presence of CD28 mutations suggests inhibitors such as abatacept may be effective against the disease. 
New research suggests cutaneous T-cell lymphoma (CTCL) is driven by a plethora of genetic mutations.
Investigators conducted a genomic analysis of normal and cancer cells from patients with CTCL and identified mutations in 17 genes that are implicated in CTCL pathogenesis.
They also found that somatic copy number variants (SCNVs) driving CTCL outnumbered somatic single-nucleotide variants (SSNVs) by more than 10 to 1.
The team reported these findings in Nature Genetics.
They performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL cells and matched normal cells. And they identified genes implicated in CTCL pathogenesis by looking for:
- Genes with recurrent SSNVs altering the same amino acid more often than expected by chance
- Genes with SSNVs previously identified as recurrent mutations in other cancers
- Genes having a significantly increased burden of protein-altering SSNVs
- SCNVs that occurred more often than expected by chance.
This revealed mutations in 17 genes that are implicated in CTCL pathogenesis—TP53, ZEB1, ARID1A, DNMT3A, CDKN2A, FAS, NFKB2, CD28, RHOA, PLCG1, STAT5B, BRAF, ATM, CTCF, TNFAIP3, PRKCQ, and IRF4.
The investigators noted that these are genes involved in T-cell activation, apoptosis, NF-κB signaling, chromatin remodeling, and DNA damage response.
The team also discovered “a striking bias” for SCNVs as drivers of CTCL. They identified 12 statistically significant chromosome-arm SCNVs and 36 significant focal SCNVs.
Collectively, these SCNVs occurred 473 times in the CTCL samples analyzed—a mean of 7.5 focal deletions, 1.6 broad deletions, 1.0 focal amplification, and 1.8 broad amplifications per CTCL.
On the other hand, there were 38 SSNVs in CTCL driver genes—1.0 per tumor.
So, according to these data, SCNVs comprise 92% of all driver mutations in CTCL—a mean of 11.8 pathogenic SCNVs vs 1.0 SSNV per CTCL.
“This cancer has a very distinctive biology,” said Jaehyuk Choi, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut.
And decoding this biology has revealed potential treatment approaches, according to Dr Choi and his colleagues.
For example, the presence of mutations activating the NF-κB pathway suggests NF-κB inhibitors such as bortezomib may have therapeutic potential in CTCL, and the presence of CD28 mutations suggests inhibitors such as abatacept may be effective against the disease.
New research suggests cutaneous T-cell lymphoma (CTCL) is driven by a plethora of genetic mutations.
Investigators conducted a genomic analysis of normal and cancer cells from patients with CTCL and identified mutations in 17 genes that are implicated in CTCL pathogenesis.
They also found that somatic copy number variants (SCNVs) driving CTCL outnumbered somatic single-nucleotide variants (SSNVs) by more than 10 to 1.
The team reported these findings in Nature Genetics.
They performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL cells and matched normal cells. And they identified genes implicated in CTCL pathogenesis by looking for:
- Genes with recurrent SSNVs altering the same amino acid more often than expected by chance
- Genes with SSNVs previously identified as recurrent mutations in other cancers
- Genes having a significantly increased burden of protein-altering SSNVs
- SCNVs that occurred more often than expected by chance.
This revealed mutations in 17 genes that are implicated in CTCL pathogenesis—TP53, ZEB1, ARID1A, DNMT3A, CDKN2A, FAS, NFKB2, CD28, RHOA, PLCG1, STAT5B, BRAF, ATM, CTCF, TNFAIP3, PRKCQ, and IRF4.
The investigators noted that these are genes involved in T-cell activation, apoptosis, NF-κB signaling, chromatin remodeling, and DNA damage response.
The team also discovered “a striking bias” for SCNVs as drivers of CTCL. They identified 12 statistically significant chromosome-arm SCNVs and 36 significant focal SCNVs.
Collectively, these SCNVs occurred 473 times in the CTCL samples analyzed—a mean of 7.5 focal deletions, 1.6 broad deletions, 1.0 focal amplification, and 1.8 broad amplifications per CTCL.
On the other hand, there were 38 SSNVs in CTCL driver genes—1.0 per tumor.
So, according to these data, SCNVs comprise 92% of all driver mutations in CTCL—a mean of 11.8 pathogenic SCNVs vs 1.0 SSNV per CTCL.
“This cancer has a very distinctive biology,” said Jaehyuk Choi, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut.
And decoding this biology has revealed potential treatment approaches, according to Dr Choi and his colleagues.
For example, the presence of mutations activating the NF-κB pathway suggests NF-κB inhibitors such as bortezomib may have therapeutic potential in CTCL, and the presence of CD28 mutations suggests inhibitors such as abatacept may be effective against the disease.